A causal analysis of the relationship between exposure to sunlight and colorectal cancer risk: A Mendelian randomization study.

Several observational studies have found that exposure to sunlight reduces the risk of colorectal cancer (CRC). However, sun exposure remains ambiguous in its relationship to CRC. We carried out a Mendelian randomization (MR) study to explore the potential associations between them. We examined the exposure to sunlight summary statistics of the UK Biobank Consortium using a 2-sample MR analysis. Using data from the FinnGen consortium, we derived summary statistics for CRC. We conducted our analysis with various methods, incorporating inverse variance weighted (IVW) along with 4 other approaches. A Cochran Q statistic was used to measure the heterogeneity of instrumental variables (IVs). We screened 133 single nucleotide polymorphisms (SNPs) (time spent outdoors in summer), 41 SNPs (time spent outdoors in winter), and 35 SNPs (frequency of solarium/sunlamp use) representing sunlight exposure for MR analysis. All selected SNPs had an F-statistic >20, indicating that IVs did not weakly bias the results. The summer outdoor activity trait exhibited significant heterogeneity (Cochran Q statistic = 183.795, P = .002 < 0.05), but we found no horizontal polymorphisms or significant heterogeneity for the other exposure traits. According to IVW estimates, no causal association exists between time spent outdoors in summer and CRC (Odds Ratio, OR = 0.735, 95% confidence interval, CI = 0.494-1.017, P = .128 > 0.017). No causal relationship existed between time spent outdoors in winter and CRC, as indicated by Bonferroni-corrected adjusted p-values. The OR was 0.877 with a 95% CI of 0.334-2.299, and the P value was .789, more significant than the significance threshold of 0.017. The solarium/sunlamp use frequency was not associated with CRC (OR = 1.567, 95%CI = 0.243-10.119, P = .637 > .017). Also, an IVW with random effects was applied to determine the causal relationship between summer outdoor time and CRC. No causal association between summer outdoor time and CRC was found (OR = 0.735, 95% CI = 0.494-1.017, P = .128 > .017). Additionally, 4 additional analyses yielded similar results. The findings of our study suggest that exposure to sunlight may reduce CRC risk, but the causal relationship remains unsolved. There is no evidence to suggest that exposure to sunlight prevents CRC. Randomized, controlled trials are needed to determine whether sunlight exposure protects against CRC.

Functional characterization of two flowering repressors SHORT VEGETATIVE PHASE and TERMINAL FLOWER 1 in reblooming bearded Iris (Iris spp.).

Reblooming bearded iris (Iris spp.) could bloom in both spring and autumn, which has extended the ornamental periods. Our previous transcriptome analysis has indicated the possible regulatory role of SHORT VEGETATIVE PHASE (SVP) in reblooming of bearded iris. Moreover, it has been revealed that the mutations of TERMINAL FLOWER 1 (TFL1) led to the continuous-flowering phenotypes in rose (Rosa spp.) and strawberry (Fragaria spp.). In order to verify the functions of these two genes on reblooming in bearded iris, IgSVP and IgTFL1 were isolated and functionally characterized. All the overexpression Arabidopsis lines of IgSVP and IgTFL1 generated the late-flowering phenotypes, indicating their functions as flowering repressors. The ectopic expression of IgSVP and IgTFL1 also generated phenotypic changes on flowers, inflorescences and branch structures. Moreover, the protein-protein interaction was found between a homologue of IgSVP and the floral meristem identity gene APETALA 1. The expression profiling showed that IgSVP was expressed significantly lower in the rebloomers in the second floral initiation stage (T5) than those of the first one (T1) in both the once-bloomers and the rebloomers, suggesting the possible regulation of IgSVP on reblooming. However, the expression level of IgTFL1 in the rebloomers was significantly higher in T5 than that in T1. The functional characterization of the two important flowering repressors IgSVP and IgTFL1 could lay solid foundation for future molecular breeding of iris, for example, knocking out the key repressors by CRISPR/Cas9 system to extend the ornamental periods of bearded iris.

Comparison between models for detecting hepatocellular carcinoma in patients with chronic liver diseases of various etiologies: ASAP score versus GALAD score.

BACKGROUND: Diagnostic panels based on multiple biomarkers and clinical characteristics are considered more favorable than individual biomarker to diagnose hepatocellular carcinoma (HCC). Based on age, sex, alpha-fetoprotein (AFP), and protein induced by vitamin K absence II (PIVKA-II) with/without AFP-L3, ASAP and GALAD models are potential diagnostic panels. The diagnostic performances of these two panels were compared relative to HCC detection among patients with various etiologies of chronic liver diseases (CLDs). METHODS: A multicenter case-control study recruited CLDs patients with and without HCC from 14 Chinese hospitals. The etiologies of CLDs included hepatitis B virus (HBV), hepatitis C virus (HCV), alcoholic liver disease (ALD), and nonalcoholic fatty liver disease (NAFLD). Using area under the receiver operating characteristic curve (AUC) values, the diagnostic performances of ASAP and GALAD models were compared to detect HCC among patients with various etiologies of CLDs. RESULTS: Among 248 HCC patients and 722 CLD controls, the ASAP model demonstrated the highest AUC (0.886) to detect HCC at any stage, outperforming the GALAD model (0.853, P = 0.001), as well as any individual biomarker (0.687-0.799, all P < 0.001). In the subgroup analysis of various CLDs etiologies, the ASAP model outperformed the GALAD model to HCC independent of CLDs etiology. In addition, the ASAP model performed better in detecting early-stage (BCLC stage 0/A) HCC versus the GALAD model. CONCLUSIONS: Despite using one less laboratory variable (AFP-L3), the ASAP model demonstrated better diagnostic performance than the GALAD model to detect all-stage HCC among patients with various etiologies of CLDs-related HCC.

Monolithic 6 × 6 transmitter-router with simultaneous sub-nanosecond port and wavelength switching.

A monolithic 6 × 6 transmitter-router with both port and wavelength switching at sub-nanosecond speed is proposed and experimentally demonstrated. Based on an intra-cavity cyclic echelle diffraction grating router (EDGR) and semiconductor optical amplifier (SOA) arrays, each selectable output port can realize a selected multi-wavelength laser (MWL) output. The measurement results show that all 36 input-output combinations have a single-mode emission spectrum with a sidemode suppression ratio (SMSR) over 30 dB. Simultaneous switching of six laser wavelengths is achieved together with the switching of the output port by a single electrode selection. The switching time is less than 1 ns. It can offer a cost-effective solution to multi-wavelength multi-port optical transmitter-routers for fast distributed optical switching in datacenters and high-performance computers (HPCs).

Effects of different photoperiods on flower opening, flower closing and circadian expression of clock-related genes in Iris domestica and I. dichotoma.

The circadian clock can entrain to forced light-dark cycles by adjusting the phases and periods of flower opening and closing in ephemeral flowers. The responses of circadian rhythms to the same light conditions differ from species. However, the differences in internal genetic mechanisms underlying the different responses between species remain unclear. Iris domestica and I. dichotoma have ephemeral flowers and significantly divergent flower opening and closing times. The effects of different photoperiods (continuous darkness, 4L20D, 8L16D, 12L12D, 16L8D, 20L4D and continuous white light) on flower opening and closing, and expression patterns of seven genes (CRYPTOCHROME 1, PHYTOCHROME B, LATE ELONGATED HYPOCOTYL, PSEUDO RESPONSE REGULATOR 95, PHYTOCHROME INTERACTING FACTOR 4-like, SMUX AUXIN UP RNA 64-like and senescence-associated gene 39-like) involved in the circadian regulation of flower opening and closing were compared between I. domestica and I. dichotoma. Flower opening and closing in the two species exhibited circadian rhythms under continuous darkness (DD), but showed arrhythmia in continuous white light (LL). In the two species, keeping robust rhythms, strong synchronicity, rapid progressions of flower opening and closing and reaching full opening stage required a dark period longer than 4 h. In light-dark cycles with dark periods longer than 4 h, flower opening and closing times of the two species delayed with the delay of dawn, and the degree to which flower opening time varies with the time of dawn was greater in I. dichotoma than in I. domestica. The arrhythmia of flower opening and closing under 20L4D and LL would result from the arrhythmic output signals rather than arrhythmia of oscillators and photoreceptors. The different responses of the two species to the change of photoperiods would be caused by the transcriptional differences of genes in the output pathway of circadian clock system rather than in the input pathway or oscillators.

Transition from metabolically healthy to unhealth status associated with risk of carotid artery plaque in Chinese adults.

OBJECTIVE: We aimed to evaluate the association between the shift of metabolic status and future risk of carotid artery plaque (CAP) in community-based Chinese adults. METHODS: The current study included 9836 Chinese adults (4085 males and 5751 females, mean age 35.8 years) with metabolically healthy status at baseline (2013). Metabolically healthy status was defined as no self-reported history of metabolic diseases and cancer, and normal blood pressure, fasting blood glucose, glycated hemoglobin A1c level, and lipid profiles. Metabolically unhealthy status was defined if any of the following metabolic abnormalities were confirmed twice during follow up: high blood pressure, impaired glucose regulation, high triglycerides, high total cholesterol, high low-density lipoprotein cholesterols, or low high-density lipoprotein cholesterols. The transition was confirmed if participants' metabolic status shifted from baseline healthy to unhealthy status during follow up (2014-2018). RESULTS: We have identified 133 incident cases of CAP during follow up. Compared to those who remained metabolically healthy, the transition to high blood pressure, high total cholesterol, and high low-density lipoprotein cholesterols, were associated with high risk of developing carotid artery plaque (Hazards ratios (HRs) ranged from 1.69 to 2.34; p < 0.05 for all). The transition to impaired glucose regulation, high total triglycerides, and low high-density lipoprotein cholesterols, were associated with high risk of carotid artery plaque only in participants with metabolically healthy overweight at baseline (HR ranged from 1.95 to 4.62; p < 0.05 for all). CONCLUSION: The transition from baseline metabolically healthy status to unhealth status was associated with high risk of incident CAP.

Metabolically healthy obesity is associated with longitudinal changes in high-density lipoprotein cholesterol in Chinese adults.

PURPOSE: Whether metabolically healthy obesity (MHO) is associated with longitudinal changes in high-density lipoprotein cholesterol (HDL-C) remains unclear. METHODS: MHO was defined as participants with overweight and obesity (BMI ≥ 24.0 kg/m2, n = 2921), free of history of metabolic diseases, and without abnormalities of blood pressure, fasting blood glucose, hemoglobin A1c, lipid profile, carotid artery and liver ultrasonographic findings at baseline. Metabolically healthy normal weight (MHN) was defined as participants with normal weight (BMI < 24.0 kg/m2, n = 9578) and without above-mentioned abnormalities. HDL-C, fasting blood glucose, hemoglobin A1c, and blood pressure were assessed annually. Glucose abnormality was considered if either FBG ≥ 5.6 mmol/L or HbA1c ≥ 5.7%; while, high blood pressure (HBP) was considered if either systolic blood pressure ≥ 130 mmHg or diastolic blood pressure ≥ 80 mmHg during 5 years of follow-up. RESULTS: Compared with the MHN group, the adjusted mean difference in HDL-C change rate was - 0.005 mmol/L per year [95% confidence interval (CI) - 0.007, - 0.003] for MHO after adjustment for a series of potential confounders. Furthermore, transiting to abnormality of blood glucose, but not high blood pressure, was associated with lower cumulative average of HDL-C in MHN group, compared with those remained in metabolically healthy status. CONCLUSIONS: MHO and transiting from metabolically healthy to abnormality of blood glucose were associated with HDL-C in Chinese adults. LEVEL OF EVIDENCE: III, cohort study.

BMI, high-sensitivity C-reactive protein and the conversion from metabolically healthy to unhealthy phenotype in Chinese adults: a cohort study.

OBJECTIVE: We performed the cohort study to evaluate the association between BMI, high-sensitivity C-reactive protein (hs-CRP) and the conversion from metabolically healthy to unhealthy phenotype in Chinese adults. DESIGN: Metabolically healthy was defined as participants without history of metabolic diseases and with normal fasting blood glucose level, glycated Hb A1c level, blood pressure, lipid profile, serum uric acid level and liver ultrasonographic findings at baseline. Participants were either classified into normal weight (18·5 ≤ BMI < 24·0 kg/m2) and overweight (BMI ≥ 24·0 kg/m2) based on baseline BMI, or low (<1 mg/l) and high (≥1 mg/l) groups based on baseline hs-CRP. The conversion from metabolically healthy to unhealthy phenotype was deemed if any of the metabolic abnormalities had been confirmed twice or more during 5 years of follow-up. RESULTS: Included were 4855 (1942 men and 2913 women, aged 36·0 ± 8·9 years) metabolically healthy Chinese adults. We identified 1692 participants who converted to metabolically unhealthy phenotype during the follow-up. Compared with their counterparts, the adjusted hazards ratio of the conversion was 1·19 (95 % CI 1·07, 1·33) for participants with overweight, while it was 1·15 (95 % CI 1·03, 1·29) for those with high hs-CRP level (≥1 mg/l). Further adjustment of hs-CRP did not materially change the association between BMI and the conversion. However, the association between hs-CRP and the conversion was not significant after further adjustment of BMI. The sensitivity analysis generated similar results to main analysis. CONCLUSION: BMI was associated with the risk of the conversion from metabolically healthy to unhealthy status in Chinese adults.

The change in kidney function was associated with carotid artery plaque in a community-based population: A cohort study.

BACKGROUND AND AIMS: We performed the current study to evaluate the association between dynamic change in estimated glomerular filtration rate (eGFR) and the risk of carotid artery plaque (CAP) in a community-based population. METHODS AND RESULTS: A total number of 37,093 Chinese adults (21,790 men and 15,303 women, aged 42.6 ± 11.6 years) free of chronic kidney diseases were enrolled. The change in eGFR was calculated based on two measurements in 2013 and 2014 (mean interval: 1.2 y). Participants were further classified into three groups based on the change in eGFR: fast-decrease (<-3.3%), stable (from -3.3% to 3.3%), and fast-increase (≥3.3%). CAP was annually assessed by ultrasound B model throughout the study (2013-2018). We have identified 1,624 new cases of CAP (16.0 per 1000 person-year) during follow up. Compared to participants with stable eGFR, participants in both fast-decrease and fast-increase groups were associated with 1.99 folds (HR = 1.99, 95% CI: 1.54, 2.57) and 3.15 folds (HR = 3.15, 95% CI: 2.38, 4.16) higher likelihood of developing CAP. The association between continuous change in eGFR and the risk of CAP demonstrate a "U" shape. Sensitivity analysis generated similar results with main analysis. CONCLUSIONS: Both fast decrease and increase in eGFR were associated with the risk of developing CAP in Chinese adults.

To bloom once or more times: the reblooming mechanisms of Iris germanica revealed by transcriptome profiling.

BACKGROUND: The reblooming bearded iris (Iris germanica) can bloom twice a year, in spring and autumn. The extended ornamental period makes it more popular and brings additional commercial values. However, little is known about the reblooming mechanisms, making the breeding programs time-consuming and labor-wasting. Therefore, a comparative transcriptome profiling was conducted on once-bloomers and rebloomers from the same F1 generation on six development stages, and the candidate genes associated with reblooming were identified. RESULTS: A total of 100,391 unigenes were generated, the mean length being 785 bp. In the three comparisons (the floral initiation stage of spring flowering in once-bloomers (OB-T1) vs the floral initiation stage of spring flowering in rebloomers (RB-T1); RB-T1 vs the floral initiation stage of autumn flowering in rebloomers (RB-T5); OB-T1 vs RB-T5), a total of 690, 3515 and 2941 differentially expressed genes (DEGs) were annotated against the public databases, respectively. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis focused on the photoperiod response, the temperature insensitivity and the growth speed, to remove the redundant DEGs and figure out the candidate key genes. As a result, the following four genes, PHYTOCHROME A (PHYA), GIGANTEA (GI), SHORT VEGETATIVE PERIOD (SVP) and AUXIN RESPONSE FACTOR (ARF), were considered to be involved in the second floral initiation of the rebloomers. CONCLUSION: This research provides valuable information for the discovery of the reblooming-related genes. The insights into the molecular mechanisms of reblooming may accelerate the breeding of bearded iris and other perennials.

The trajectory of high sensitivity C-reactive protein is associated with incident diabetes in Chinese adults.

BACKGROUND: We performed a cohort study to evaluate the association between the CRP trajectory and incident diabetes in Chinese adults. METHODS: Included were 6439 adults (4111 men and 2249 women; aged 46.6 ± 11.9 years). The concentration of high sensitivity CRP (hs-CRP) was measured in 2013 (baseline), 2014, and 2015. The hs-CRP trajectory was identified based the above three measurements by latent mixture modeling. Incident diabetes cases were diagnosed by fasting blood glucose (≥126 mg/dl) or Hb A1c (≥6.5%) during subsequent 3 years (2016-2018). RESULTS: Hs-CRP concentration during 2013-2015 was classified into 3 levels: low (< 1.0 mg/L), moderate (1.0-3.0 mg/L), and high (≥3.0 mg/L) based on a statement by American Heart Association. We named four hs-CRP trajectories as following: "low-stable" (low in 2013 and maintained at low concentration in 2014 and 2015), "moderate-fluctuated" (moderate in 2013, then increased to high concentration in 2014, and decreased to low concentration in 2015), "high-decreased" (high in 2013 but decreased to moderate concentration in 2014 and 2015), and "moderate-increased (moderate in 2013 and increased to high concentration in 2014 and 2015)". We identified 235 incident diabetes during subsequent 3 years. The adjusted HR for incident diabetes was 1.71 (95% CI: 1.02, 2.87) comparing the moderate-increased and the low-stable group, after adjusting for potential confounders. In the secondary analyses, two single-measured hs-CRP concentration (in 2013 or in 2015) and the average of hs-CRP were associated with high risk of diabetes (P-trend< 0.01 for all). CONCLUSIONS: The hs-CRP trajectory pattern was associated with altered incident diabetes in Chinese adults.

The Relationship between Red Blood Cell Distribution Width and Incident Diabetes in Chinese Adults: A Cohort Study.

BACKGROUND: Previous studies reported the controvertible association between red blood cell distribution width (RDW) and diabetes. The aim of this study is to explore whether RDW is associated with incident diabetes. METHODS: We performed this cohort study in 16,971 Chinese adults (9,956 men and 7,015 women, aged 43.3 ± 12.8 years). The level of RDW was measured at baseline (2014). All the participants were further classified into four quartile groups based on baseline RDW. Fasting blood glucose (FBG) and glycated hemoglobin A1c (HbA1c) were measured annually during follow-up (2014-2019). Diabetes was diagnosed if either FBG ≥ 7.0 mmol/L or HbA1c ≥ 6.5%. We used the Cox proportional hazards regression model to evaluate the association between baseline RDW and incident diabetes. RESULTS: We identified 2,703 new cases of diabetes during five-year follow-up. The incidence was 15.9%. Comparing with participants in the lowest quartile group (reference group), the adjusted hazard ratios (HR) for the risk of diabetes were 1.31 (95% CI: 1.16, 1.48) for the highest quartile group (p trend < 0.001), after adjustment for potential confounders. Further adjusting baseline FBG and HbA1c did not materially change the association between RDW and incident diabetes. Each unit increase of RDW was associated with a 16% higher risk of incident diabetes (HR = 1.16, 95% CI: 1.06, 1.26) in a fully adjusted model. Sensitivity analysis generated similar results with prospective analyses after excluding aged participants, participants who are overweight and with obesity, participants with elevated blood pressure, participants with decreased eGFR, and those with anemia at baseline. CONCLUSIONS: High RDW was associated with high risk of developing diabetes in Chinese adults. As RDW is an inexpensive, noninvasive, and convenient indicator, RDW might be considered for inclusion in the risk assessment of high-risk groups of diabetes.

Association between non-alcoholic fatty liver disease and silent carotid plaque in Chinese aged population: a cross-sectional study.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a risk factor for carotid plaque in the general population; however, whether NAFLD is associated with carotid plaque in aged population remains unknown. This cross-sectional study was conducted to evaluate the association between NAFLD and carotid plaque in a Chinese aged population. METHODS: A total number of 12,990 Chinese aged adults (7,685 men and 5,305 women) were included. NAFLD was diagnosed based on the recommendation of Asia-Pacific Working Party on NAFLD and Chinese Association for the Study of Liver Disease and excessive alcohol consumption (weekly alcohol consumption ≤210 g in men and ≤140 g in women) was excluded. Carotid plaque was confirmed by ultrasonography. Potential confounders and biochemical findings were collected at baseline. Logistic regression model was employed to evaluate the association between NAFLD and carotid plaque. RESULTS: The prevalence of carotid plaque was significantly higher in aged participants with NAFLD than in those without NAFLD (22.4% vs. 16.3%, P<0.001). NAFLD is associated with carotid plaque [odd ratio (OR) =1.89, 95% confidence interval (CI): 1.59-2.24], after adjusting for age, gender, BMI, liver and kidney function, glucose level, lipid profiles, and white blood cell (WBC) count. The association between NAFLD and carotid plaque was attenuated when participants with elevated ALT (≥75 IU/L), a history of cardiovascular diseases (CVDs) and obesity were censored although the significant association remained. CONCLUSIONS: NAFLD is associated with carotid plaque in Chinese aged population.

Comprehensive Analysis of Serum and Fecal Bile Acid Profiles and Interaction with Gut Microbiota in Primary Biliary Cholangitis.

Accumulation of bile acids (BAs) contributes significantly to the pathogenesis of primary biliary cholangitis (PBC). Here, we sought to systematically characterize the serum and fecal BA profiles and the linkage between BAs and gut microbiota in PBC. The serum and fecal BAs were compared between 65 UDCA treatment-naive PBC and 109 healthy controls using UPLC-MS in cross-sectional study. In a prospective study, a subgroup of patients was enrolled for BA and microbiota analysis before and after UDCA therapy. BA compositions in serum and feces significantly differed between treatment-naive PBC and controls. Particularly, PBC was associated with decreased conversions of conjugated to unconjugated, and primary to secondary BAs, indicating impaired microbial metabolism of BAs. PBC patients at advanced stage exhibited a more abnormal BA profile compared with early-stage patients. UDCA treatment led to a decreased level of taurine-conjugated BAs, thereby reversing the conjugated/unconjugated ratio in PBC. Moreover, the level of secondary BAs such as DCA and conjugated DCA inversely correlated with PBC-enriched gut microbes (e.g., Veillonella, Klebsiella), while positively correlated with control-enriched microbes (e.g., Faecalibacterium, Oscillospira). Microbiota analysis also revealed a significant increase of taurine-metabolizing bacteria Bilophila spp. in patients after UDCA, which was strongly correlated with decreased taurine-conjugated BAs. In addition, serum FGF19 was remarkably increased in treatment-naïve PBC and decreased after UDCA. Our study established specific alterations of BA compositions in serum and feces of PBC, suggesting the potential for using BAs for diagnosis, and highlighting the possibility of modulating BA profile by altering gut microbiota. Graphical Abstract.

Reduction of mitochondria and up regulation of pyruvate dehydrogenase kinase 4 of skeletal muscle in patients with chronic kidney disease.

AIM: Muscle weakness is commonly among chronic kidney disease (CKD) patients. Muscle mitochondrial dysfunction and decreased pyruvate dehydrogenase (PDH) activity occur in CKD animals but have not been confirmed in humans, and changes in pyruvate dehydrogenase kinase (PDK) and pyruvate dehydrogenase phosphatase (PDP) expression have not been evaluated in CKD muscle. We presume that the reduction of muscle mitochondria and post-translational modification of PDH may cause muscle weakness in CKD patients. Herein, we explored changes in mitochondrial morphology, PDH expression and activity, and PDK/PDP expression in CKD patient muscle. METHODS: Twenty patients with stage 4-5 CKD (CKD group) and 24 volunteers (control group) were included. Clinical characteristics, biochemical information and handgrip strength (HGS) were determined. Skeletal muscle samples were collected from eight stage 5 CKD patients from CKD group. Other eight non-CKD surgical subjects' muscle samples were collected as control. PDH activity was determined using a PDH enzyme activity assay kit, and real-time PCR and western blotting analyses were performed to measure gene expression and protein levels, respectively. Transmission electron microscopy was used to study mitochondria morphology. RESULTS: CKD patients had lower HGS than non-CKD subjects, and HGS was correlated with gender, age, haemoglobin and albumin. Mitochondria were decreased in end-stage renal disease (ESRD) patients muscle. Mfn-1 expression and phospho-Drp1(S637)/Drp1 ratio were inhibited in the ESRD group, implicating dysfunctional mitochondrial dynamics. Muscle PDH activity and phospho-PDH(S293) were decreased in ESRD patient muscle, while PDK4 protein level was up regulated. CONCLUSION: Decreased mitochondria and PDH deficiency caused by up regulation of PDK 4 contribute to muscle dysfunction, and could be responsible for muscle weakness in CKD patients.

Alterations of gut microbiome in autoimmune hepatitis.

OBJECTIVE: The significance of the liver-microbiome axis has been increasingly recognised as a major modulator of autoimmunity. The aim of this study was to take advantage of a large well-defined corticosteroids treatment-naïve group of patients with autoimmune hepatitis (AIH) to rigorously characterise gut dysbiosis compared with healthy controls. DESIGN: We performed a cross-sectional study of individuals with AIH (n=91) and matched healthy controls (n=98) by 16S rRNA gene sequencing. An independent cohort of 28 patients and 34 controls was analysed to validate the results. All the patients were collected before corticosteroids therapy. RESULTS: The gut microbiome of steroid treatment-naïve AIH was characterised with lower alpha-diversity (Shannon and observed operational taxonomic units, both p<0.01) and distinct overall microbial composition compared with healthy controls (p=0.002). Depletion of obligate anaerobes and expansion of potential pathobionts including Veillonella were associated with disease status. Of note, Veillonella dispar, the most strongly disease-associated taxa (p=8.85E-8), positively correlated with serum level of aspartate aminotransferase and liver inflammation. Furthermore, the combination of four patients with AIH-associated genera distinguished AIH from controls with an area under curves of approximately 0.8 in both exploration and validation cohorts. In addition, multiple predicted functional modules were altered in the AIH gut microbiome, including lipopolysaccharide biosynthesis as well as metabolism of amino acids that can be processed by bacteria to produce immunomodulatory metabolites. CONCLUSION: Our study establishes compositional and functional alterations of gut microbiome in AIH and suggests the potential for using gut microbiota as non-invasive biomarkers to assess disease activity.

A Novel Online Calculator Based on Serum Biomarkers to Detect Hepatocellular Carcinoma among Patients with Hepatitis B.

BACKGROUND: Early detection of hepatocellular carcinoma (HCC) among hepatitis B virus (HBV)-infected patients remains a challenge, especially in China. We sought to create an online calculator of serum biomarkers to detect HCC among patients with chronic hepatitis B (CHB). METHODS: Participants with HBV-HCC, CHB, HBV-related liver cirrhosis (HBV-LC), benign hepatic tumors, and healthy controls (HCs) were recruited at 11 Chinese hospitals. Potential serum HCC biomarkers, protein induced by vitamin K absence or antagonist-II (PIVKA-II), α-fetoprotein (AFP), lens culinaris agglutinin A-reactive fraction of AFP (AFP-L3) and α-l-fucosidase (AFU) were evaluated in the pilot cohort. The calculator was built in the training cohort via logistic regression model and validated in the validation cohort. RESULTS: In the pilot study, PIVKA-II and AFP showed better diagnostic sensitivity and specificity compared with AFP-L3 and AFU and were chosen for further study. A combination of PIVKA-II and AFP demonstrated better diagnostic accuracy in differentiating patients with HBV-HCC from patients with CHB or HBV-LC than AFP or PIVKA-II alone [area under the curve (AUC), 0.922 (95% CI, 0.908-0.935), sensitivity 88.3% and specificity 85.1% for the training cohort; 0.902 (95% CI, 0.875-0.929), 87.8%, and 81.0%, respectively, for the validation cohort]. The nomogram including AFP, PIVKA-II, age, and sex performed well in predicting HBV-HCC with good calibration and discrimination [AUC, 0.941 (95% CI, 0.929-0.952)] and was validated in the validation cohort [AUC, 0.931 (95% CI, 0.909-0.953)]. CONCLUSIONS: Our results demonstrated that a web-based calculator including age, sex, AFP, and PIVKA-II accurately predicted the presence of HCC in patients with CHB. CLINICALTRIALSGOV IDENTIFIER: NCT03047603.

Prospective study of hemoglobin A1c and incident carotid artery plaque in Chinese adults without diabetes.

BACKGROUND: Diabetes has been reported to be associated with carotid artery plaque (CAP). However, it remains unclear whether hemoglobin A1c (HbA1c) level, a marker for long-term glycemic status, is associated with altered CAP risk in individuals with fasting blood glucose (FBG) concentrations below the current cutoff for diabetes. METHODS: Included were 16,863 Chinese adults (aged 18 years or more; 9855 men and 7008 women) with fasting blood glucose < 7.0 mmol/L at baseline (2013). Both HbA1c level and CAP (assessed via ultrasound B-mode imaging) were annually assessed during 2014-2018. All the participants were further classified into three groups based on baseline HbA1c level: ≤ 5.6%, 5.7-6.4%, and ≥ 6.5%. We used Cox proportional-hazards model to evaluate the association between HbA1c level and incident CAP, adjusting for a series of potential confounders. RESULTS: During 5 years of follow up, 3942 incident CAP cases were identified. Individuals with higher baseline HbA1c had higher future risk of CAP (p-trend < 0.001). In the full-adjusted model, each percent increase of HbA1c was associated with a 56% (HR = 1.56, 95% CI 1.37, 1.78) higher risk of CAP. Excluding participants with chronic inflammation, as assessed by high-sensitivity C-reactive protein and white blood cell, and those with FBG ≥ 5.6 mmol/L at baseline generated similar results. CONCLUSIONS: Elevated HbA1c level was associated with high risk of developing CAP in Chinese adults without FBG defined diabetes.

Association of Metabolically Healthy Overweight Phenotype With Abnormalities of Glucose Levels and Blood Pressure Among Chinese Adults.

Importance: Whether the metabolically healthy overweight (MHO) phenotype is resistant to metabolic abnormalities remains unknown. Objective: To evaluate the association of MHO with glucose level abnormalities and high blood pressure (BP) in Chinese adults. Design, Setting, and Participants: This prospective cohort study was conducted from January 1, 2013, to October 31, 2018, in the Health Management Center at Ren Ji Hospital, Shanghai, China, using data from 55 155 recruited Chinese adults. Body weight, fasting blood glucose (FBG) level, hemoglobin A1c (HbA1c) level, and BP were measured annually. Exposures: Metabolically healthy overweight was defined as a body mass index (calculated as weight in kilograms divided by height in meters squared) of 24.0 in 2013 (baseline) and 2014, no history of metabolic diseases, and normal FBG level, HbA1c level, BP, lipid profile, serum uric acid level, and liver ultrasonographic findings at baseline; the remaining participants were defined as being metabolically healthy normal. Main Outcomes and Measures: Glucose level abnormality was confirmed if the FBG level was 101 mg/dL or greater or the HbA1c level was 5.7%, and high BP was confirmed if the systolic BP was 130 mm Hg or higher or the diastolic BP was 80 mm Hg or higher at least twice during the subsequent 4 years of follow-up. Results: A total of 3204 metabolically healthy Chinese adults (mean [SD] age, 39.8 [10.9] years; 1940 women [60.5%]) were included in the study. The prevalence of MHO was 7.0%. A total of 146 incident cases of glucose level abnormality and 220 cases of high BP during 4 years of follow-up were identified. Compared with the metabolically healthy normal group, the MHO group had a higher risk of glucose level abnormality (adjusted hazard ratio, 2.36; 95% CI, 1.52-3.64) and high BP (adjusted hazard ratio, 1.73; 95% CI, 1.18-2.53) after adjusting for several potential confounders. Conclusions and Relevance: Metabolically healthy overweight may be associated with a high future risk of glucose abnormality and high BP in Chinese adults. If the individuals are confirmed with MHO, early interventions, including diet and exercise, should be recommended to decrease the risk of developing abnormalities of glucose and BP.